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Title	Insights into eosinophilic esophagitis using computational genomics and bioinformatics
Publication Type	dissertation
School or College	School of Medicine
Department	Human Genetics
Author	Lin, Edwin
Date	2019
Description	Eosinophilic esophagitis (EoE) is an immune-mediated disease of the esophagus that is commonly triggered by food antigens. EoE was uncharacterized prior to 1993, but it is now the most common cause of dysphagia (difficulty swallowing) and food impaction requiring esophageal endoscopy. EoE causes acute food impaction that requires emergency endoscopic removal. Chronic EoE causes fibrostenotic stricture formation and esophageal remodeling, and patients require periodic esophageal dilatation in order to eat. The mechanism of fibrosis in EoE is poorly studied, and optimal prevention strategies are unknown. EoE is diagnosed by endoscopic biopsy, which is invasive and incurs significant costs for patients. Food antigens that trigger EoE are determined through diet elimination trials, which can span years and consist of routine, near-monthly biopsies. This dissertation focuses on three clinical needs for EoE patients, which are the following: 1) to investigate the mechanism of fibrosis, 2) to develop a noninvasive diagnostic modality, and 3) to develop a method for rapid identification of trigger antigens. We used RNA-seq and histopathologic validation to show that a subepithelial immunoregulatory response is characteristic of EoE and can induce fibrosis. We used RNA-seq and quantitative protein assays to discover diagnostic biomarkers in esophageal secretions collected by noninvasive brushing. Finally, we developed an assay to accurately predict trigger foods using food-specific antibodies in esophageal secretions. These research methods were applied to other diseases. We performed the first characterization of eosinophilic granulomatosis with polyangiitis, a rare and fatal systemic vasculitic disease, and identified possible pathogenic mechanisms and drug targets. We are the first to perform deep-sequencing of cell-free DNA and machine learning to distinguish between hormone-sensitive and castration-resistant metastatic prostate cancer, and to identify targetable genomic alterations associated with disease progression. These demonstrate the broad utility of computational genomics for translational medicine.
Type	Text
Publisher	University of Utah
Dissertation Name	Doctor of Philosophy
Language	eng
Rights Management	© Edwin Lin
Format	application/pdf
Format Medium	application/pdf
ARK	ark:/87278/s6tc2jp6
Setname	ir_etd
ID	1947865
Reference URL	https://collections.lib.utah.edu/ark:/87278/s6tc2jp6

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Title	Page 66
Format	application/pdf
Setname	ir_etd
ID	1947931
OCR Text	Show 56 oesophagitis. a comprehensive prospective study using five modalities. Alimentary Pharmacology & Therapeutics, 44(3):223–233, Jun 2016. [9] Frederic Clayton, John C Fang, Gerald J Gleich, Alfredo J Lucendo, Jose M Olalla, Laura A Vinson, Amy Lowichik, Xinjian Chen, Lyska Emerson, Kristen Cox, Molly A O’Gorman, and Kathryn A Peterson. Eosinophilic esophagitis in adults is associated with IgG4 and not mediated by IgE. Gastroenterology, 147(3):602–609, Sep 2014. [10] Benjamin L Wright, Mike Kulis, Rishu Guo, Kelly A Orgel, W Asher Wolf, A Wesley Burks, Brian P Vickery, and Evan S Dellon. Food-specific IgG4 is associated with eosinophilic esophagitis. The Journal of Allergy and Clinical Immunology, 138(4):1190– 1192.e3, Apr 2016. [11] Chen E Rosenberg, Melissa K Mingler, Julie M Caldwell, Margaret H Collins, Patricia C Fulkerson, David W Morris, Vincent A Mukkada, Philip E Putnam, Tetsuo Shoda, Ting Wen, and Marc E Rothenberg. Esophageal IgG4 levels correlate with histopathologic and transcriptomic features in eosinophilic esophagitis. Allergy, 73(9):1892–1901, Jun 2018. [12] Simon Weidlich, Simon Nennstiel, Moritz Jesinghaus, Knut Brockow, Julia SlottaHuspenina, Monther Bajbouj, Roland M Schmid, and Christoph Schlag. Igg4 is elevated in eosinophilic esophagitis but not in gastroesophageal reflux disease patients. Journal of Clinical Gastroenterology, 54(1):43–49, Jan 2019. [13] Alexander J Schuyler, Jeffrey M Wilson, Anubha Tripathi, Scott P Commins, Princess U Ogbogu, Patrice G Kruzsewski, Barrett H Barnes, Emily C McGowan, Lisa J Workman, Jonas Lidholm, Sheryl L Rifas-Shiman, Emily Oken, Diane R Gold, Thomas A E Platts-Mills, and Elizabeth A Erwin. Specific IgG4 antibodies to cow’s milk proteins in pediatric patients with eosinophilic esophagitis. The Journal of Allergy and Clinical Immunology, 142(1):139–148.e12, Jul 2018. [14] Lawrence Zukerberg, Krishnan Mahadevan, Martin Selig, and Vikram Deshpande. Oesophageal intrasquamous IgG4 deposits: an adjunctive marker to distinguish eosinophilic oesophagitis from reflux oesophagitis. Histopathology, 68(7):968–976, Jun 2016. [15] Nissreen Mohammad, Vishal Avinashi, Edmond Chan, Bruce A Vallance, Elodie Portales-Casamar, and Jonathan W Bush. Pediatric eosinophilic esophagitis is associated with increased lamina propria immunoglobulin g4-positive plasma cells. Journal of Pediatric Gastroenterology and Nutrition, 67(2):204–209, Aug 2018. [16] Kelly M O’Shea, Seema S Aceves, Evan S Dellon, Sandeep K Gupta, Jonathan M Spergel, Glenn T Furuta, and Marc E Rothenberg. Pathophysiology of eosinophilic esophagitis. Gastroenterology, 154(2):333–345, 2018. [17] Oliver Pabst. New concepts in the generation and functions of IgA. Nature Reviews. Immunology, 12(12):821–832, Dec 2012. [18] Satu Sulkanen, Tuula Halttunen, Kaija Laurila, Kaija L Kolho, Ilma R KorponaySzabó, Annikki Sarnesto, Erkki Savilahti, Pekka Collin, and Markku Mäki. Tissue transglutaminase autoantibody enzyme-linked immunosorbent assay in detecting celiac disease. Gastroenterology, 115(6):1322–1328, Dec 1998.
Reference URL	https://collections.lib.utah.edu/ark:/87278/s6tc2jp6/1947931